Psychiatry & Psychotherapy Podcast - Nortriptyline and the Tricyclic Antidepressants with Dr. Cummings

Episode Date: September 15, 2020

In today's episode of the podcast, we'll be doing a deep-dive into nortriptyline, a lesser-talked about medication in psychopharmacology. We'll cover a little about the history of tricyclic antidepressants (TCAs) as well as the characteristics, side-effects, and indications to consider when prescribing this class of medication. By listening to this episode, you can earn 0.75 Psychiatry CME Credits. Link to blog. Link to YouTube video.

Hello and welcome to the Psychiatry and Psychotherapy Podcast. I'm here to talk about getting rid of burnout, increasing job satisfaction, and feeling like an expert in what you do. One thing that created a lot of burnout and angst for me was trying to get continued medical education right at the last minute. So why not join the CME membership and do CMEE while listening to this podcast? Go to Psychiatrypodcast.com, sign up, sign in, take the test, and the certification is email to you in seconds.

Hi, welcome back to the podcast. Today I am joined with Dr. Michael Cummings. episode we are going to be doing a deep dive into tricyclic antidepressants specifically nortriptylene. We'll be going through the history of tricyclic antidepressants and where they fit in the timeline of the history of psychiatry. We'll talk about their characteristics, adverse effects, contraindications. We'll talk about how they're used, specifically what, you know, are their current indications. We'll talk about treatment resistant depression, neuropathic pain, fibromyalgia, ADHD, smoking cessation, Parkinson's disease, migraines.

And not only is there an audio episode on this, but you can also find a more full and even more robust article on this on the website. I think this is a great episode for someone in psychiatry to understand, you know, a medication in depth. We've had a lot of popularity in the past with other episodes on like clozapine and lithium where myself and Dr. Cummings do a deep dive on the psychopharmacology. It's a good board prep, and it's also good to understand these medications that are on literally the $4 list at some pharmacies.

They're very cheap medications because they've been around for a while, and they're generic now, and they may be underutilized in some specific situations. So, welcome to the podcast. So I think people have said that the thing that they enjoy the most is these individual medications going kind of a deep dive. And so I was thinking we would do nortriptylene today because that's kind of a lesser known medication. I think I looked at a bunch of psychopharm books and like sometimes it's just a little paragraph or just even a mention. Yes. Yeah, we can also frame it and give people a bit of the background of how they tricycle.

cyclics came to be and how they are different and then get down to Nordtryptylene itself. Yeah, so maybe just start telling me a little bit about the history and then we'll get into the mechanism. Okay. Well, basically, the tricyclic antidepressants were an outgrowth of research that really started in the 1930s looking at polycyclic compounds with the initial aim of developing antihistamines. That resulted in the synthesis and release of the first antihistamine diphenhydramine in 1946. The very next year, 1947, promethethazine, was released as a

preoperative agent for calming people. That led ultimately to development of chlorpromisein, the first antipsychotic in 1950. And it was really an outgrowth of pharmaceutical firms, including one named Geigy, a Swiss firm that was looking for further antipsychotics. And they were looking for them by essentially generating compounds and sending them out to psychiatrists in Europe in small psychiatric hospitals and asking them to give medications to patients to see what would happen. Basically, were they antipsychotic? One of these in 1955 was the first tricyclic antidepressant amypremine. When it was sent for study, it frankly did not help with psychosis.

However, two things happened that clued people into the idea that it might be antidepressant. One, some people became floridly manic when they were exposed to amypramine. And the other thing that happened is some people who had prominent depressive symptoms, got remarkably better. The person who first described this was Dr. Coons, K-U-H-N-S in Switzerland. I wrote all six-page paper and presented his findings, and that set off a whole cascade of research looking for further tricyclic antidepressant medications. The two parent compounds that came into existence were amypromine and amyptylene. Both are what are term tertiary amines, meaning that the nitrogen atom on the central ring is joined to the two carbons adjacent in the ring and also to a third methyl group.

If you demethylate those two compounds, amatryptylene becomes nortryptylene, or literally the desmethyl methyl metabolite of amyptylene, and amypromine becomes desmethyptylene, and amypromine becomes desipramine, the secondary amine drugs like nortriptylene differ from the tertiary drugs in a number of ways. The tertiary drugs like amatryptylene and amypromine are much more anticholinergic. They're much better alpha antagonists, so they cause more dizziness and hypotension. They also are predominantly serotonin reuptake inhibitors. In contrast to that, nortryptylene and desipramine are both very potent norapinephrine reuptake inhibitors, so they increase norepinephrine much more than serotonin. They're fairly modest inhibitors at alpha receptors and acetylcholine receptors,

so they don't have as severe a side effect profile in that regard. like all of the tricyclics they are still however cardiotoxic the ld-50 or the amount it takes to be lethal for the tricyclic antidepressants as a group including nortryptylene is only about six to eight times the therapeutic plasma concentration which is why in groups prone to overdose people always used these drugs with a great deal of caution Yeah. Yeah, that's one pro right there is to, if you have a suspicion that they might try to overdose, these might not be the meds for them. And honestly, primary care physicians often aren't thinking about that when they give them for pain or give them for migraines. They're not thinking, oh, this person has a history of overdosing on meds a couple times. Yes. And indeed, what you've seen since the introduction of the SSRI antidepressants is the use of the use of, of tricyclic antidepressants for treatment of major depressive disorder, panic disorder, anxiety

disorders, has declined dramatically. The other things that nortryptylene has been indicated for, indeed include neuropathic pain. Interestingly, tibromandibular joint pain, although I'm not frankly quite sure why that specific pain is included, although it was demonstrated in at least two small trials to be effective for that. It also has been used as a, well, really a second or third line agent to treat attention deficit hyperactivity disorder and also as a smoking cessation agent. Not that, frankly, it seems to be a very highly effective compound for either of those

latter two conditions compared to other agents that are available. I think where you do see it used is in cases where either the other drugs are of limited availability or in areas where people may have very limited funds, because indeed, nortriptylene having been generic now for decades, it was introduced and approved by the FDA in 1964. for it's dirt cheap. On most pharmacies, if you price it per tablet, it typically sells at wholesale acquisition cost for around two or three cents a tablet.

Yeah, it's on the Amatryptylene, Nordtryptylene are both on the $4 list at Walmart, which I often go to to sort of slidylase. select medications if someone does not have insurance. Let me double check that. Yeah, it's on there. And so for 90 capsules, you can get that for $10 or for 30-day supply, you can get it for $4. That's the $4 list. Yeah.

Yeah, they're very cheap medications, which can be an advantage for people who have very limited funding. you know the probably if given that the major use is neuropathic pain or pain syndromes the doses are relatively low for most individuals for most people for neuropathic pain you're talking about doses between 10 milligrams and 25 milligrams once a day usually at bedtime to treat the disorder it's very rare to get up to 50 milligrams grams a day. Yeah, so for nortryptylene, 10 milligrams is kind of like that low-end dose, the lowest dose that you can get a pill.

Yes. Yeah, it comes in 10 milligrams, 25 milligrams, 50, and 75. Right. Unless you're treating depression, which has a dose range of 50 to 150 milligrams a day, and a plasma concentration, a range is actually a kind of. kind of parallels that, 50 to 150 nanograms per milliliter. For pain, there's no reason to ever push the doses that high. For most people with neuropathic pain, 10 milligrams to 25 milligrams at bedtime should be

sufficient. What I've found, too, is as people go up in the dose, the side effects really do crank up. the anti-colonergic side effects, the dry mouth, the fogginess, the constipation, urinary retention. So at a low dose of 10 to 25, I usually don't see those. Once you get up around 75, 100, you're going to definitely see some of those side effects. Oh, very, very definitely. because although these are listed as having only intermediate level inhibition of acetylcholine receptors and histamine receptors, and they are indeed milder than the tertiary tricyclics,

once you get above 25 to 50 milligrams a day, you start seeing more and more in the way of adverse effects. Yeah. One issue to be careful of with nortriptylene in that regard is nortriptylene is very heavily dependent, as are all of the tricyclics, on metabolism by cytochrome P450 2D6. So if the person is either a very poor metabolizer at 2D6, or should they be taking a 2D6 inhibitor like peroxitene, fluoxetine, Buproprion, you'll get dramatically higher plasma concentrations than you would expect for a given dose. Yeah, that's worth repeating because I see that all the time. I see, you know, a patient will come back.

They'll be on Prozac. They'll be on fluoxetine or Buproprion or Paxil. Proxatine. And then the general practitioner puts them on amatryptylene or nortyptylene. and both of these need that 2D6 to break down. And so when you don't have that, working as well, the level goes way up. And when the level goes way up,

they may look more depressed. But what that is, it's a hypoactive delirium. It's that anticholinergic, hitting that sensorium really, really hard. And because of that, sometimes they get referred to psychiatry because it's like, hey, I don't know what's going on. This person's more depressed.

You know, sometimes, Like, I can pick these things up. Indeed. If they suddenly look sedated, confused, weak, and they have anticholinergic physical features, odds are their blood level is way higher than you would expect for the dose they're taking. Which, again, to reemphasize the point, can also be very dangerous because I remember, nortryptylene, just like the rest of the tricyclics, has a very narrow therapeutic end. index, the amount needed to kill half of the people taking the drug is only six to eight times

the therapeutic plasma concentration range. Yeah. In the handout, I'll give a little diagram of how amatriptylene is broken down through that 2D6 pathway. Amatryptylene also breaks into other metabolites that nortriptylene doesn't have. Yeah. And in that regard, if somebody is picking a tricyclic antidepressant these days, I would encourage them to stick, very much stick with the secondary amine tricyclics

rather than choosing tertiary amine tricyclic. One, because the tertiary amypamine or amythropoline are much harder to tolerate. And two, because they do have active metabolites, it's also much easier to get the person toxic if there are things affecting their hepatic metabolism. Yeah, I think that's why I'm starting out with nortryptylene, because amotryptylene, honestly, like a lot of the patients that come in to me with that are, they seem sedated, they don't seem like themselves. You know, when patients complain about, you know, I just don't feel myself,

I feel like this medication is taking away my personality. A lot of the time, it's the sedating qualities. Yeah. So when they come in, I try to get them off of the amatryptylene and the things like cyclobenzaprine. You know, there's a lot of other very strong anticholinergic medications that patients will come on to cope, to cope with reality. And then it's like, okay, but we want to now do intensive therapy. We want them to process through things. And when they're too sedated, they can't do that.

So reducing the nortryptylene dose is sometimes something I have to do to get them to a dose that's not heavily anticholonergic. And also getting them off the amatryptylene is something that I do often. A point I also would make for people is that if you are at all suspicious that the plasma concentration of the nortryptylene is too high, This is a drug where it's very worthwhile to actually measure the plasma concentration. People vary just inherently, aside from drug interactions, they inherently vary greatly with respect to metabolic rate for nortryptylene. The half-life in the population averages 27 hours, but that has a range of 18 hours to 44 hours,

depending on how much 2D6 the person inherently has. So the amount of drug buildup can vary hugely from one person to the next. Yeah, and remember it takes about four half-lifes to get someone to that sort of steady state level. So if it's two days, then you're not really going to see what their top level is until eight days after you start the medication. And if you block that 2D6, you're changing the half-life. and so you're going to have build up. It's going to build up over potentially, you know, a week or two. So at first you may not see it.

It may take a little while. Yeah, you may not see your patient coming back saying, gee, I don't feel the same. I can't focus. I can't wake up. And what you're looking at is they've accumulated the drug over time, which at the dose is used to treat neuropathic pain, buildup is usually not a huge issue.

If you do have people, not that I'm encouraging this, but if somebody does actually want to use nortryptylene to treat a major depressive episode and needs, therefore, much higher doses, 50 to 150 milligrams a day, you really should track plasma concentrations carefully. These drugs are lethal because they inhibit cardiac conduction, all of the tricyclics do this. They impair depolarization at the AV node and bundle of his.

That results in a widening of the QRS prolongation of the QT interval, making the person very vulnerable to a fatal cardiac arrhythmia. Yeah, that's a good point. So, like, let's say you're treating them for depression. Are there any types of depression where you would kind of think of, think of nor triptylene as an option. Going back all the way to Dr. Coon's original report regarding a mypremine, which was published, I think, 1947 are presented by him in 1947, sorry, 1957, I'm a decade off.

Basically, he described what are typical antidepressant responders, that is people who have not depressed mood, but the classic neurovegetative signs and symptoms of either increased or decreased sleep, increased or decreased energy, usually decreased appetite, in other words, a predominance of neurovegetative signs and symptoms. These days, there was an impression for quite a long time that the tricyclics might be more effective for treatment-resistant depression than the other antidepressant agents, that's looking less and less true when people have compared the tricyclic response rates to the response rates for SNRIs, provided that both classes of drugs are actually given at effective therapeutic doses. And certainly the SNRIs that are available

now are much safer than the tricyclic antidepressants for treating major depression. Drugs like venal vaccine, duoxetine, milanacopran, even though it's not marketed in the U.S. as an antidepressant and levo milanacopran. Yeah, there was a study in 2003 that I found in the by Ninenberg, I'm probably pronouncing that wrong, where they looked at. this for treatment resistant depression. They took 92 patients, a mean age of 41, and these people had not responded to one,

all the way up to five antidepressant adequate trials of adequate duration, adequate doses, and then they put them on nortripterptylene for six weeks. They titrated them up to a blood level around 100 nanograms per ML, and they defined response as a 50% or greater decrease in the baseline, you know, 17-it-it-it-hampal for depression. And what they found was that about 40% of the patients were responders and 12% were remitters

after six weeks. So over about a third of, or and over a third of patients could not complete the trial because of the side effects. and that's important to note because some people are going to experience those side effects a lot more strongly. And so they kind of thought that it was an option for those that don't respond to antidepressants. But I think I agree with you that nowadays I think more Symbolta, I think, you know, and if you look at, yeah, go ahead. What led people into thinking that was indeed if you just look at the raw response rates for, tricyclics versus the raw response rates for SNRIs. The tricyclics initially look better

until you compare the placebo response rates. The placebo response rates don't match, and consequently you have to adjust for that in order to directly compare the drugs. When you statistically adjust for placebo response rates in the SNRI trials versus the tricyclic trials, the overall efficacy of the two classes essentially is the same. Now, that's not to say that if you have somebody who hasn't responded to any of the SNRIs with adjuncts, that you shouldn't, that you should never consider a tricyclic, but you should weigh very carefully the potential risks of the of the tricyclics, even the best tolerated ones like desepramine and nortriptylene, as you've pointed out, have much greater difficulty with

tolerability. And of course, you always have looming in the background the issue that these drugs are very lethal in overdose. Let me ask a question because I'm not sure that that's completely understandable to myself. So, in this, the prior trials, you're saying that the placebo response to a neurotripling compared to placebo, the placebo response was less or more than the newer trials comparing Simbalta and a placebo? The placebo response rate in the later trials, the more recent trials with the SNRIs, has tended to be higher.

And what that argues is that in the very early days of antidepressant treatment. When they picked study samples as part of their research design, they tended to pick people who were more ill. They often at that time they were not doing Hamilton depression rating scales, but my supposition would be that they were picking people whose Ham D ratings were in the 30s. You know, these were severely ill. As time has gone by and they now, do trials with depressed people, major depressive disorder. They still meet the criteria for the diagnosis, but often the cutoff for trial entry is a Hamdi score in the 20s. So essentially, you're comparing in some ways populations that have different severity of illness. And one

reflection of that is that you get more placebo responders in the more recent trials. Well, that means you can't directly compare the outcome numbers, you know, the percent of people who got better and the percent of people who got remitted because you're, in some ways, you're comparing apples and oranges because you're not comparing people who were equally ill across treatments. Yeah, I think this is a good point. And it's also a point for why you can't compare, like, effect sizes between one study and another directly, right? because the effect size will look better for the older studies that have more severe disease start points. Yeah, and that led people in this case to, I think, mistakenly think, oh, well, the tricyclics were more effective. Well, no, you're comparing, again, a different level of illness, and consequently it's not a fair comparison, and unless you is to statistically adjust for that, which mathematically you can do.

And when you do that, the effect size for the two classes, the SNRIs versus the tricyclics, looks about the same. So I think as groups, people need to drop the idea that the tricyclics are inherently more effective. They may be more effective for an individual patient, but that's different than saying, oh, as a class, they're more effective than the more recent SNRIs. You know, it's interesting I was looking at some some meta-analysis on like fibromyalgia and the change in the fibromyalgia impact questionnaire. And it does seem like you have amatryptylene, you have, seems to have some benefits in the change in pain a little bit better than something. things like malnassopram or deloxetine.

You have a little bit, the change in fatigue, it seems to be better in malnacopram. And the change in the FIQ seems to be pretty similar between amyptylene, malnacepam, phenylophaxine, deloxetine being a little bit lower. But yeah, what do you think about specifically with pain and maybe fibromyalty? I think with pain in particular, one of the reasons you may see a bigger effect with the tricyclics in some studies, not all, is you're getting a much better antihistaminic effect than with the SNRI drugs. You're sedating the person slightly. And indeed, one of the, aside from directly inhibiting ascending pain pathways with increased norephenephrine,

you're also dulling the cortical ability to appreciate pain. So you may get a bigger subjective effect than with the SNRIs. Okay. Which is why it may be reasonable, even in people who are being treated with melnasopran or elinelanacepan, for example, for fibromyalgia or neuropathic pain. and they're just not having an adequate response, for example, they're still having a lot of trouble sleeping because of nocturnal pain. That may be the patient in whom a small dose of nortryptylene at bedtime

may benefit them greatly. One of the things to be aware of with the S&RIs is they vary quite a bit among themselves in terms of their re-uptick inhibition. If you put serotonin in the left-hand column and noraphenephyrine in the right-hand column for the SNRI's vinula-faxine is 30-to-one serotonin. Duoxetine is 10-to-one serotonin. Melanacephan is one-to-one, equal,

both serotonin and norapherin and levo-elanacophan is one-to-two. It's the most noradrenergic of the of the SNRIs in comparison doesopramine and nortryptylene are also about like the livo monasopran they're they're more noradrenergic than serotonergic yeah it's um nor triptylene i'm looking at the the k i values it's about 10 times more norinergic than serotonergic um yes and uh that's interesting So, yeah, I'm seeing a lot of...

That's one of the reasons that, yeah, one of the reasons that, for example, desert amine is contraindicated in children and a nortripylene is certainly dubious in children is these drugs simply because the neuroadrenergic effect can trigger cardiac arrhythmia's in children. Yeah, you know, there is a black box warning, age less than 25. increased risk of suicidality. Do you have any thoughts on that with nortriptoleen specifically? That also is true of nortyptylene. I'm frankly old enough that I was around and trained back in the day when tricyclics were common. The observation that was made later with SSRIs and increased suicidal thoughts applies to the older antidepressants as well. If you look carefully

at the studies, it may be true of all antidepressants. When we treat people for major depressive disorder, frankly, we improve their neurovegetative signs and symptoms faster earlier than we improve their mood. So we go through a phase where we have now an energized depressed person. That may be the highest risk period for suicidal ideation and suicidality. if you're sort of a depressed person who's also a sloth, well, you may not act on any negative thoughts you have, but if we give you energy and you're depressed, you're at higher risk. Now, when the FDA issued their warning for the SSRIs,

their intent was to say, okay, don't give the person an antidepressant and say, oh, come back and see me in a month. Their intent was that you see the person sooner and evaluate them for suicidal thoughts, suicide risk, risk. Unfortunately, the effect of their warning was to decrease the prescribing of antidepressants, which actually did then increase the suicide rate. So it's more an issue of be aware that initially during treatment, likely all antidepressants increased suicide risk. So bring back the person sooner rather than later and ask them whether they're having increased thoughts,

increased impulses with respect to suicide. Yeah, and I think, you know, in regards to suicide completion, I've looked at this quite a bit. It seems like about half of people who complete suicide are not in any treatment for the period of time before, you know, the actual suicide event. and further, you know, if you look at places in the world where you have higher density of psychiatrists, psychotherapists, there's often a lower rate of suicide. So these things I think point for me that treatment is very important and we are doing good work. We are. There was a survey done at least two decades ago now.

I'd have it would be hard to find. but I remember being impressed at the time I read it. I was done by the American Psychiatric Association at that time looking at the adequacy of antidepressant treatment. And in primary care settings, only 41% of people were judged to receive adequate antidepressant treatment. Now, frankly, at that time, the psychiatrist did better, but it didn't do well enough. I think the number for the psychiatrist was around two-thirds, 65%. Hopefully, both we and the primary care physicians have gotten better since then. But you're absolutely right.

The more treatment people have, the better their odds of getting better and also of not completing suicide. You know, and to bring this to the current time that we're in, I don't know if you saw that recent CDC, document that came out August 17th, but they talked about how the suicidal thoughts is going way up. And the percentage in this group that they looked at, it's like a lot higher than I would have expected. What do you think? Yeah, this pandemic is putting enormous stresses on people, certainly financial stress, loss of stability. being simply confined and unable to access usual social supports. All of those things are, I think, adding up to, frankly, we're going to have a sub-epidemic,

if you will, of social isolation, loneliness, depression, and suicidality related to the COVID pandemic. Okay. listen to this quote from this article. The percentage of respondents who reported having seriously considered suicide in the 30 days before completing the survey was 10.7% was significantly higher among respondents age 18 to 24. That jumped up to 25%. Racial minorities, ethnic groups, Hispanics were 18.6%. Black respondents were 15.1%. But listen to this.

Self-reported unpaid caregivers for adults was 30.7%. And essential workers, 21.7%. That seems really high to me. That seems really high. That is really high. And frankly, those are somewhat frightening numbers. But if you think about it, unpaid caregivers and essential workers have,

in many ways face the most stress during this pandemic. They're often, literally, they are on the front lines in terms of demands on them. And at the same time, there's often a diminishing or absence of psychosocial supports. I think this brings us back in many ways to the fact that we are inherently a social species. And when we have something this socially disruptive and demanding at the same time, it is really a major destabilizing influence on people's mental health. Listen to this. The unpaid caregivers had an increase in substance use to 32.9% versus the other population at 6.3% suicidal ideation

30.7% versus 3.6% in this in the other group. It's such a huge difference. And I see it. We had a lady come over to our house with her daughter and she's been doing the homeschooling. She's been working full time

and she hasn't been connecting with other human beings. And I think that the social, it's the lack of social support. I mean, she had this like oral hunger. She just needed to talk, you know, and we felt it really intensely. Yes. And I'm feeling that from so many of my clients right now, just this like loneliness, this despair, this disconnection, you know, from things that they used to find connecting. Well, you know, people have been isolated from other people. They've been isolated from the activities they use to keep themselves stable. And in many

cases, people have been asked for essential workers, okay, they're still employed, they're working, which is a good thing, but it's a demand. They're also providing care at home. They've also, in many cases, become the school teacher. Those are enormous demands. Yeah. So if you're listening to this and you're in that, you know, place where you also need help, don't, don't feel afraid to reach out. You know, this is a good time to, to pull into some of the resources that you can connect with, you know, even if, as health care givers, you know, the people that are on the forefront, we are also, I think, more exhausted, more stressed because, you know, not only is our jobs often increased in demand and the patients have increased in severity. But as well, we come home to family

structures and family systems that have been stressed out, kids that haven't had the normal connections with friends, you know, partners that may be more stressed out in their roles as well. So I think it's just been a tough time for all of us. And so it's good to get help. I personally have been seen a therapist once a week, which I wasn't before this, but I realized I needed to get back into that. And so Yeah, I highly recommend it to people who are listening to this. Okay. Well, let's get back to Nordtryptylene.

Man, I almost want to cut that out and make that a separate episode. Just a mini, like, just a mini, like, episode. Maybe I'll do that. But let's finish this North Triptolline discussion. Okay. So one thing I wanted to talk about where I think this might still have a role, and I'd be curious your perspective is in Parkinson's disease. So in one study, they compared nortriptylene with placebo and peroxatine,

and they found nortriptylene more effective than the peroxatine, then the placebo. Yeah, do you have any thoughts on Parkinson's disease specifically? Specifically in Parkinson's disease, the tricyclics, in particular nortyptylene, can be useful in a small number of cases. In particular, the drug is helpful, of course, with the dysphoria associated with Parkinson's disease. Its neuroduringic activity does support greater alertness and cognition. And, of course, because it's anticholinergic, it also can assist with motor symptoms. So I'm not surprised that it was a better drug than placebo or the SSRIs,

which are not nearly as robust with respect to noradrenergic activity, as you pointed out. The ratio is, you know, 10 to 1 over serotonin for norapherent, for neurotryptylene. And it's also intermediate potency in terms of being anticholinergic. Yeah, I wonder just because it does have some anticholinergic, whereas Melnasopran does not have any anticholinergic properties. I'm wondering if I might consider Melasopran or the cousin of, what was the cousin of Melnasopram that you mentioned? Livo Melnasopram. Yeah, I wonder if I would consider those for Parkinson's before. I would. One of the things that I and the group I work with are putting together, it's actually in press now with Cambridge University Press, is a small handbook basically on management of complex treatment resistant psychosis. But a part of that book includes a section that covers all of the tricyclic antidepressants.

and basically the consensus statement for the take-home pearls for all of them is these are not first-line drugs these days for anything, but they may be worth considering if other options, safer drugs, either don't work or not available. Yeah. So another thing that I see this used for is migraines. Yes. I found this one paper on vestibular migraines, which I see sometimes in the MENT program that I run. It's the IOP partial that I run, or I'm the medical director of.

And there was a systemic review meta-analysis of vestibular migraines, and it did show that, you know, in a bunch of different studies, nortryptylene had a large portion, sometimes greater than 50% of people who responded with a greater than 50% improvement in those vestibular migraines, which can be fairly debilitating. And sometimes I'll see my migraine expert colleagues here at my university

put patients on nortyptylene or amatryptylene. So that's another sort of thing that I see. It's a worthwhile thought. Again, for the tricyclics, including nortryptylene, they would not be my first choice, but they would not be off the table either if other drugs were not adequately effective. And I carefully thought through the risks and benefits, then indeed, you know, a trial of amatryptylene, less so, nortriptylene more so, would be worth considering for vestibular and other migraines as well.

Yeah. Some of the other options for those types are propanolol, that seem to, have a meaningful improvement in a lot of patients and things like actually calcium channel blockers seem to have good improvement. So, okay. Probably these days the beta blockers like propranol are very often the most frequently prescribed migraine prophylaxis. But like all treatments, no single treatment works for everybody.

and it's good to have a second and third line choice like nortyptylene amatryptylene. Okay, so maybe bringing this to a conclusion, I think my summary of things that you should remember, both for the boards and for practice, is definitely understand that the three psychiatric meds that are very potent 2D6 blockers, fluoxetine, peroxitine, bupropriotone, understand that those can increase any tricyclic,

specifically amatryptylene, nortriptylene, you can have increased levels and then increased potential toxicity. You know, six times the therapeutic dose, you get into that toxic range where it could kill 50% of the people on it. So that would be one pearl to take away. The second pearl would be careful in people

who have a risk of overdose. This probably isn't a medication you want, want to give a 90-day supply to someone who has a high risk of overdosing. And the third big takeaway is that for pain, you can use smaller doses, and sometimes that's enough. And so a small dose of 10 to 25, nor triptylene may be indicated in someone with pain issues and not needing to reach that full antidepressant dose. What are some of your pearls or do you have any additions to what I just mentioned?

One, I agree with your pearls. The one I would add to that is if you have any suspicion that this person is a poor 2D6 metabolizer, do not hesitate to measure a plasma concentration. Plasma concentrations have gotten fairly cheap, and they are a great way to know exactly how much drug is in the person. You know, doses by comparison are very crude, inaccurate measures of how much treatment you're actually delivering. Plasma concentrations give you a very precise measure, not only of how much drug is present, but also directly reflect, is this person a good or poor absorber and metabolizer of the drug in question,

including nortryptylene? and for the tricyclics, how much drug is present is critical to know because of the potential toxicities. Yeah, on that point, I used to do genetic testing. I don't anymore just because I feel like it doesn't give me a whole lot of information that's useful and it's very expensive. But when I did, I found one patient who was unable to metabolize 2D6 at all. And not surprisingly, she had a very poor...

response to tricyclics years ago when she had tried them just for a couple days. So, yeah. Yeah, the plasma levels are far cheaper and give you essentially the same information. I think they give you more information, actually. The more, that's one thing I think I've learned from you, Dr. Cummings, because it's not just their P450s that change the plasma concentration. It's also the meds they're on. and their body type and, you know, so many different things can contribute to that.

If they have a ruin why, that can, or some sort of gastric bypass, that can change plasma concentrations as well. And so, yeah. Yeah, indeed. Okay. Yeah, any final, any final thoughts, or you think we're good to go on this one? I think we're probably good. All right. I hope this has been helpful for you. If you want to check out the resources, we'll put on the web, website psychiatrypodcast.com. We'll put the, you know, the notes and some citations. You can take a look at things. I'll put this really good chart that I found of the K values, how tightly different medications are binding. I think that that's worthy to look at to sort of understand this further. And I hope you have a great day.